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Subtype-specific effects of clonal hematopoiesis on cerebrovascular and cardiometabolic disease risk

Wenqiang Zhu1, Miao Tian1, Zihan Zhao2

  • 1Department of Internal Medicine, Division of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.

Frontiers in Neurology
|May 14, 2026
PubMed

Insights

Clonal hematopoiesis of indeterminate potential (CHIP) impacts cerebrovascular risk differently based on its genetic subtype. TET2-CHIP shows the most consistent associations with stroke and hypertension, highlighting distinct clinical consequences.

Area of Science:

  • Genetics
  • Cardiovascular Medicine
  • Hematology

Background:

  • Aging populations often exhibit clustered cardiometabolic and cerebrovascular diseases, linked to metabolic dysfunction and inflammation.
  • Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition associated with inflammation, metabolic issues, and vascular risk.
  • The specific impact of CHIP subtypes on cerebrovascular outcomes within the cardiometabolic context requires further investigation.

Purpose of the Study:

  • To investigate causal links between CHIP, its genetic subtypes, and cerebrovascular/cardiovascular diseases.
  • To examine cancer outcomes as a broader systemic context for CHIP.
  • To validate biological mechanisms of key CHIP subtypes through in vitro experiments.

Main Methods:

  • Mendelian randomization analyses were used for overall CHIP and five subtypes (DNMT3A, TET2, JAK2, TP53, ASXL1).
  • Associations were assessed with 20 cerebrovascular/cardiovascular diseases and 19 site-specific cancers.
  • In vitro experiments explored the biological role of TET2-CHIP under inflammatory and metabolic stress.

Main Results:

  • CHIP demonstrated significant heterogeneity across cerebrovascular and cardiovascular outcomes.
  • TET2-CHIP showed strong associations with ischemic stroke, intracerebral hemorrhage, and hypertension.
  • ASXL1-CHIP indicated elevated risk for intracerebral hemorrhage and hypertension; JAK2-CHIP showed inverse associations with intracerebral hemorrhage and atrial fibrillation; DNMT3A-CHIP linked to atrial fibrillation and abdominal aortic aneurysm.
  • Cancer analyses revealed additional subtype-specific associations.
  • Experimental studies confirmed TET2 deficiency's role in promoting macrophage lipid accumulation, inflammation, and endothelial dysfunction.

Conclusions:

  • CHIP is linked to subtype-specific cerebrovascular risks within the cardiometabolic spectrum.
  • TET2-CHIP emerged as the most consistently associated subtype with cerebrovascular outcomes.
  • The heterogeneity across CHIP subtypes underscores the need to view CHIP as mutation-defined conditions with distinct clinical impacts, not a uniform entity.
Abstract

Keywords:
Mendelian randomizationcardiometabolic riskcerebrovascular diseaseclonal hematopoiesis of indeterminate potential (chip)stroke

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